The primary objective of this proposal is to define the factors that influence glomerular subepithelial localization of immune complexes. These studies will utilize the well characterized Heymann rat model of membranous nephropathy. Prior investigations have generated controversy regarding the in situ versus circulating immune complex mechanisms for subepithelial deposit formation. Recent data from our laboratory have confirmed that both mechanisms play a role in the development of Heymann nephritis. Preliminary results suggest that chemical features unique to the antigen in Heymann nephritis, as well as properties of the antibody may favor the subepithelial site of localization of the immune complexes in this animal model of membranous nephropathy. This proposal is designed to clarify these factors. Interactions between the glomerular capillary wall and the renal tubular antigen will be evaluated following further purification of the antigen. The influence of antibody affinity on the clearance of the circulating complexes by the mononuclear phagocyte system and site of tissue localization will be determined. Understanding the role of antibody affinity has therapeutic implications for human membranous nephropathy. Confirmation of the association of higher antibody affinity with milder disease would suggest that immunostimulation of production of high affinity antibody may be successful therapeutic approach. This would be an important advance as all current treatment which includes immunosuppression has been only moderately beneficial. The final goal of this proposal is to define the relative contribution of each mechanism of subepithelial deposit formation, circulating immune complex and in situ binding, to the full development disease.